Use of propionyl-carnitine or one of its pharmacologically acceptable salts for the preparation of a medicine for the treatment of la peyronie&#39;s disease

ABSTRACT

The invention described herein relates to the use of propionyl L-carnitine or one of its pharmaceutically acceptable salts for the preparation of a medicine useful for the treatment of La Peyronie&#39;s disease in its various stages, particularly at the advanced stage and in forms resistant to conventional therapies. The medicine is suitable for oral, intramuscular, intravenous, and intraplaque administration. The invention described herein also relates to a combination of an active ingredient in the treatment of La Peyronie&#39;s disease, particularly verapamil, and propionyl L-carnitine or one of its pharmaceutically acceptable salts. Propionyl L-carnitine has proved to be more effective than the known active ingredients, also in intractable forms, and presents a lower incidence of side effects.

The invention described herein relates to the use of propionylL-carnitine or one of its pharmacologically acceptable salts for thepreparation of a medicine useful in the treatment of La Peyronie'sdisease.

BACKGROUND TO THE INVENTION

La Peyronie's disease is an inflammatory condition still of largelyunclear aetiology (probably hereditary-based autoimmune) affecting thetunica albuginea of the penis. This inflammation is self-maintaining andis prevalently sectorial (Belgrano E. et al. ed. Induratio PenisPlastica: Stato Dell'Arte. Ospedaletto (Pisa); Pacini Editore, 1999).Only in some cases, in fact, does it affect other sheaths of the body(palmar aponeurosis, retroperitoneal fascia). One can distinguishbetween three stages of La Peyronie's disease, namely, acute, earlychronic and late chronic (advanced), each with its own histological,symptomatological and physical and instrumental semeiologicalcharacteristics. The stages are determined on the basis of symptoms,physical examination, colour Doppler ultrasonography andhistopathological models. Though the models of the disease areconsistent, the same cannot be said of its duration, extent and severity(Davis C, J. Urol. 1997; 157; 272-5). Currently, there exist a wholeseries of pharmacological and physical remedies in the therapy of LaPeyronie's disease, which is probably the disease associated with thelargest number of non-surgical attempts at treatment, owing to thepaucity of case-control studies and the peculiarity that the diseaseprogresses in some 10-20% of cases despite the therapy (forms indicatedherein as “resistant La Peyronie's disease”).

The therapy of the disease is now well standardised from the point ofview of the timing of therapy: the first approach in order of time ispharmacological, and then later, whenever the progression of the diseasehas been arrested and medical therapy has proved insufficient to remedythe deformity of the penis or the erectile deficit induced by LaPeyronie's disease, surgical therapy is resorted to. The first approach(medical) consists in the administration of drugs via several routes andis mainly indicated in the acute and early chronic stages (Belgrano,ibid). Various drugs have been tried, such as tocopherols, vitamin E,para-aminobenzoic acid, allopurinol, colchicines, immunomodulators andtamoxifen. Apart from the tocopherols, vitamin E and allopurinol, theother drugs have shown a certain measure of efficacy, which is alsopredictable on a scientific basis, but present the occurrence ofunwanted side effects such as gastrointestinal symptoms, reduced libido,skin rashes, and fever in 18-33% of patients, thus limiting orcontraindicating their use (Belgrano, ibid.).

The occurrence of side effects and sometimes difficulties with themanageability of certain drugs (immunomodulators, tamoxifen) have posedthe problem of the need to look for alternative drugs for the treatmentof La Peyronie's disease. This search is aggravated by the fact thatthere are currently no reliable experimental models of La Peyronie'sdisease. Effectively speaking, reports have recently been published onthe induction of La Peyronie's-disease-like lesions in rats by theinjection of the cyctokine, transforming growth factor beta 1, into thetunica albuginea. This substance transforms fibrocytes into fibroblastsand increases vascularisation and vascular permeability by inducingangiogenesis. (El-Sakka A. L, et al. Br. J. Urol. 1998, 81:445-52;Bivalacqua T. J, et al. J. Androl. 2001, 22:497-506; Bivalacqua T. J.,et al. J. Urol. 2000, 163:1992-8; El-Sakka A. L, J. Urol. 1997,158:2284-90). This model is based on the assumption, reiterated severaltimes by the authors, that La Peyronie's disease is due to anexaggerated cicatricial response following a genital trauma. This viewmust be regarded as superseded by the hypothesis that the disease isbased on a hereditary autoimmunity of two types, one consisting in thetotal penetrance of an autosomal dominant gene probably related to theHLA (histocompatibility) locus of chromosome 6 (rare form—1 case out of4—which is inherited from father to son) and the other in partialpenetrance (more frequent) in which a predisposition to fibrosclerosingautoimmune diseases is inherited (Belgrano E., ibid.; Aynaud O.,Casanova J. M.: Pathologie de la Verge. Masson, Parigi 1998). Moreover,the experimental model is induced, whereas human La Peyronie's diseasearises spontaneously. This model is based on injection into the tunicaalbuginea of transforming growth factor beta 1, which is a cytokineproduced by the endothelium both in the inflammatory phase (Miculeck A.A., et al. Arch. Facial Plast. Surg. 2001: 3: 111-114) and in the courseof an increased metabolic requirement (Fasciani A., et al. Fertil.Steril. 75: 1218-1221, 2001), and is therefore an entirely aspecificcytokine (and thus experimental model). What is more, in La Peyronie'sdisease, as in all other forms of inflammation of the body, a largequantity of cytokines are secreted, which, when generically injectedinto a mammal, cause inflammation in a completely aspecific manner(Belgrano E., ibid.; Aynaud O., Casanova J. M., ibid.).

The experimental model implies that the erectile deficit secondary to LaPeyronie's disease is due to an arterial deficiency. Recent research,however, has shown that the erectile deficit secondary to La Peyronie'sdisease is secondary to a venous deficiency (Belgrano E., ibid.; AynaudO., Casanova J. M. ibid.).

Furthermore, La Peyronie's disease, being a form of inflammation oflikely autoimmune origin, is self-maintaining and mainly sectorial, asmentioned above, whereas this is not the case in the experimental model.

At the present time there are no reliable experimental models of LaPeyronie's disease, since it constitutes a form of inflammation of asyet unknown pathogenesis.

Two case-control studies using drugs are currently known to have beenconducted, one comparing acetyl-carnitine versus tamoxifen (BiagiottiG., Cavallini G.: BJU International (201), 88, 63-67) and the othertamoxifen versus placebo (Teloken C., et al. J. Urol. 162 2003-2005,1999) in a patient population not selected on the basis of stage.

No case-control studies are known to exist on the advanced stages of thedisease; moreover, in the literature there are no reports on Petronie'sdisease resistant to medical therapy, which constitutes a class destinedto remain unhealed, where even surgery is not a feasible proposition(reserved exclusively for those subjects in whom progression of thedisease has been arrested by medical therapy) and no wholly reliablepharmacological therapy is yet available.

Medical therapies for La Peyronie's disease sometimes entail modes ofadministration which are distinctly unpleasant for the patient:subcutaneous injections adjacent to the plaque (Brake M. et al.; BJUInt. 2001, May; 87(7):654-657, where, amongst other things, theunsatisfactory outcome of treatment with interferon 2β is reported);local injections of betamethasone, hyaluronidase and lidocaine; orintralesional injections of verapamil (Lamprakopulos A. et al. Scand. J.Urol. Nephrol. 2000 December; 34(6):355-360; Rehman et al. Urology,1998, April,; 51(4); 620-626).

In addition to the extensive scientific literature, the patentliterature reports various different methods of treating the diseasewith different active ingredients, see, for example, WO 01/27479,Androsolutions, which involves the administration of drugs via anintrapenile catheter; WO 01/09178, Incyte Genomics, that utiliseschaperonine; the various Vivus Inc patents (U.S. Pat. No. 6,113,393;U.S. Pat. No. 5,925,629, U.S. Pat. No. 5,773,020, U.S. Pat. No.5,474,535 and EP 0 526 566), and many others, in which the most commonlyindicated administration modes are of the intraurethral type. Otherpatents worthy of mention are U.S. Pat. No. 6,093,181, BR 9801985 (oneof the few to provide a topical treatment with a cream), U.S. Pat. No.6,033,374, U.S. Pat. No. 6,031,005, EP 1 097 202, U.S. Pat. No.6,022,539, EP 0 986 417, and U.S. Pat. No. 4,338,300.

It is therefore necessary to have a therapy for La Peyronie's diseasethat matches up to the requirements of efficacy with an administrationmode which is well accepted by the patient, e.g. by mouth, and that isalso capable of resolving cases resistant to the known treatments.

The aim of the invention described herein is to meet these requirementsand solve the above-mentioned problems.

Propionyl L-carnitine is known to have numerous therapeutic uses: forexample, U.S. Pat. No. 4,415,859 describes its use, together with otherlower acyl carnitines, for the treatment of diseases of the veins, suchas venous stasis, the aetiology of which is based on the reducedelasticity of the erythrocyte wall. European Patent EP 0 793 962describes the use of propionyl L-carnitine in the treatment of Stage 2chronic obliterating atherosclerosis according to the Leriche Fontaineclassification (intermittent claudication), a disease of the lower limbscaused by an inadequate blood supply to the muscles. U.S. Pat. No.5,869,528 describes the use of L-carnitine and the lower acylL-carnitines, including propionyl, in the treatment of attention deficitand hyperactivity disorder (ADHD). U.S. Pat. No. 6,013,670 describes theuse of propionyl L-carnitine in the intrarectal treatment of chronicinflammation of the bowel. All the above-mentioned patents are filed inthe name of the Applicant.

A propionyl L-carnitine-based drug is commercially available in Italyunder the trade name Dromos®, indicated for the treatment ofobliterating arteriopathy of the lower limbs and for the therapy ofchronic congestive heart failure in order to increase the tolerance ofphysical effort (see also patent GB 2,008,578).

No efficacy of propionyl L-carnitine has ever been described in thetreatment of diseases such as La Peyronie's disease characterised byfibrotic tissue.

In the above-cited article by Biagiotti and Cavallini (BJU International88: 63-67, 2001) it was demonstrated that acetyl L-carnitine issignificantly more active than tamoxifen in the treatment of LaPeyronie's disease in the early stages. In this study the authorslimited the use of acetyl L-carnitine only to the oral treatment of theacute and early chronic stages, stating that the more severe chronic andresistant states were intractable with oral therapy alone. Since theaetiology of La Peyronie's disease has yet to be fully clarified(Hellstrom W J and Bivalacqua T J, J. Androl. 2000 May-June;

-   -   21(3):347-54), it is putatively suggested that, on the basis of        several of its known properties, acetyl L-carnitine may        conceivably play a role in the inflammation and fibrosis typical        of the disease without, however, in any way suggesting the use        of propionyl L-carnitine, which, in any event, is a different        molecule.

Propionyl L-carnitine has proved capable of affording protection inexperimental animal models (rats) against forms of chemically inducedinflammation of both the skin and the arteries (Amico-Roxas M. et al.Drug Exptl. Clin. Res. 19: 213-217, 1993; Corsico N. et al., Cardiovasc.Drugs Ther. 7: 341-351, 1993), this property not being shared by acetylL-carnitine and L-carnitine. It should be noted that the animal modelused by Amico Roxas et al. Is not in any way transferable to or evenpredictive for a fibrosis-based disease such as La Peyronie's. The Roxasmodel, in actual fact, is a model of cutaneous inflammation induced bychemical agents, whereas in the case of La Peyronie's disease anautoimmune pathogenesis is postulated (Belgrano e al. ibid.).

Various considerations based on the existing state of knowledge of thecarnitine system substantiate the claim that this difference in activitybetween acetyl L-carnitine and propionyl L-carnitine in Amico Roxas etal.'s inflammation model is not attributable to a greaterbio-availability of the different acyl esters at tissue level, since theamount bound and that present in solution in plasma are the same andcannot be modified by external inputs (Marzo A. et al., Eur. J. DrugMetab. Pharmacokinet. 3:364-368, 1991), but only by actual biochemicaldifferences between the respective esters.

SUMMARY OF THE INVENTION

It has now been found that propionyl L-canitine is effective in thetreatment of La Peyronie's disease to an even greater extent than acetylL-carnitine.

Accordingly, one object of the invention described herein is the use ofpropionyl L-carnitine or one of its pharmaceutically acceptable saltsfor the preparation of a medicine useful for the treatment of LaPeyronie's disease, in its various different forms and stages,particularly in the acute, early chronic and late chronic stages and inthe resistant forms. In particular, said medicine is suitable for oral,intravenous, intramuscular and intraplaque administration.

Another object of the invention described herein is a combination ofpropionyl L-carnitine, or an equivalent amount of one of itspharmaceutically acceptable salts, and one or more ingredients active inthe therapy of La Peyronie's disease. Though no restrictions apply withregard to the type of active ingredient to be used in the therapy of LaPeyronie's disease, the following substances are indicated by way ofexamples: tocopherols, vitamin E, allopurinol, potassium aminobenzoate(POTABA), tamoxifen, immunomodulators, triamcinolone, and verapamil. Theexpert in the sector is capable of determining the active ingredient inthe therapy of La Peyronie's disease on the basis of his or her generalknowledge, such as, for example, the above-cited report by Belgrano andthe literature cited in this patent application.

In one particular aspect of the invention, the combination consists ofpropionyl L-carnitine and verapamil.

Said combination can be formulated in a pharmaceutical composition,which is also an object of the invention described herein, useful as amedicine for the treatment of La Peyronie's disease.

Propionyl L-carnitine lends itself to the treatment of La Peyronie'sdisease in its broadest definition, but has proved particularly usefulin patients with La Peyronie's disease at the chronic advanced stageand, surprisingly, in patients with La Peyronie's disease resistant toother “conventional” forms of therapy.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention described herein, propionyl L-carnitine canbe used both in the form of an inner salt, which is in itselfpharmaceutically acceptable, and in the form of a salt with apharmaceutically acceptable acid.

What is meant by pharmaceutically acceptable salt of propionylL-carnitine is any of its salts with an acid that does not give rise tounwanted toxic or side effects.

Such acids are well known to pharmacologists and to experts inpharmaceutical technology.

Examples of such salts, though by no means constituting a complete list,are: chloride, bromide, orotate, acid aspartate, acid citrate, magnesiumcitrate, acid phosphate, fumarate and acid fumarate, magnesium fumarate,lactate, maleate and acid maleate, mucate, acid oxalate, pamoate, acidpamoate, acid sulphate, glucose phosphate, tartrate, acid tartrate,magnesium tartrate, 2-amino-ethane-sulphonate, magnesium2-amino-ethane-sulphonate, 2-amino-ethane-sulphonate chloride, glycinechloride, choline tartrate, taurinate and trichloroacetate.

In an initial realisation form of the invention described herein, themedicine containing propionyl L-carnitine is suitable for oraladministration.

In the case of the combination of propionyl L-carnitine and anotheractive ingredient, as seen above, particularly verapamil, such acombination lends itself to co-ordinated use.

Within the context of the invention “for co-ordinated use” of theaforementioned compounds what is meant, indifferently, is either anyform of co-administration, i.e. the essentially simultaneous orsequential administration of propionyl L-carnitine or one of itspharmacologically acceptable salts and the other active ingredient, orthe administration of a composition containing the aforesaid activeingredients in a combination and mixture, in addition to excipients, ifany.

In this context, the medicine, or the pharmaceutical compositiondescribed here below, containing the combination, shall be formulated insuch a way as to allow the administration of the two active ingredientsin the different modes envisaged for co-ordinated use. In a preferredrealisation of this aspect of the invention described herein, saidmedicine is suitable for the oral administration of propionylL-carnitine and for the intraplaque administration of verapamil.

The medicine, particularly for co-ordinated use, shall be convenientlyprepared in the form of a pharmaceutical composition. According to theinvention described herein, the active ingredient shall be in a mixturewith suitable vehicles and/or excipients commonly used in pharmacy, suchas, for example, those described in “Remington's Pharmaceutical SciencesHandbook”, latest edition. The compositions according to the inventionshall contain a therapeutically efficacious amount of the activeingredient. The dosages and modes of administration, even when envisagedfor co-ordinated use, shall be determined by the expert in the sector,e.g. the clinician or primary care physician, according to the type ofdisease to be treated and the patient's condition, or, concomitantlywith the administration of other active ingredients.

Examples of pharmaceutical compositions are those that allow oral orparenteral administration by the intravenous, intramuscular,subcutaneous, or transdermal routes. Suitable pharmaceuticalcompositions for the purpose are tablets, rigid or soft capsules,powders, solutions, suspensions, syrups, and solid forms for extemporeliquid preparations. Compositions for parenteral administration are, forexample, all the intramuscular, intravenous and subcutaneous forms, inthe form of solutions, suspensions and emulsions. Liposomal formulationsshould also be mentioned. Also included are the forms involving thecontrolled release of the active ingredient, both for oraladministration, including tablets coated with appropriate layers,microencapsulated powders, complexes with cyclodextrin, and depot forms,e.g. subcutaneous ones, such as depot injections or implants. Thepreferred administration forms for propionyl L-carnitine are the oral,intramuscular, intravenous and intraplaque forms.

In a preferred realisation form of the invention described herein, themedicine, particularly for co-ordinated use, is suitable for the oraladministration of 1 g of propionyl L-carnitine, or an equivalent amountof one of its pharmaceutically acceptable salts, per dosage unit, andfor the intraplaque administration of 10 mg of verapamil.

What is meant by preferred form is the mode of administration ofpropionyl L-carnitine preferred by the patients, which has been usedextensively in its oral formulation, but which has proved efficacious inthe therapy of La Peyronie's disease at the chronic advanced stage alsoin its intramuscular, intravenous and intraplaque form. Thesealternative administration routes (intramuscular or intravenous) havebeen used in cases in which the patients refused oral administration orpresented unavoidable side effects (hypotension) as a result of theintraplaque injection of verapamil.

The following examples further illustrate the invention.

The examples are based on a limited number of patients and therefore theanalysis of the results was carried out only with regard to thefundamental characteristics of the disease, namely plaque area in mm²(as measured by means of dynamic colour Doppler ultrasonography) andcurvature of the artificially erect penis induced by intracavernousinjection of 20 μg of prostaglandin E1.

EXAMPLE 1

Oral Tamoxifen Versus Intravenous Propionyl L-Carnitine

40 subjects (mean age 52, range 44-61) with induratio penis plastica (LaPeyronie's disease) at the chronic stage were randomised therapy withintravenous propionyl L-carnitine 300×2 mg/day for 3 months, and thesecond group to therapy with oral tamoxifen 20×2 mg/day. The variablesmeasured were plaque area by means of dynamic colour Dopplerultrasonography and penile curvature, which was present in 16 patientsper group. It was found that intravenous propionyl L-carnitine reducesthe plaque area and the curvature of the artificially erect penis to asignificantly greater extent than tamoxifen. Intraplaque verapamil wasnot used in these patients.

The results are presented in Table 1, where the data are expressed asmean±standard deviation (S.D.). TABLE 1 Intravenous propionylL-carnitine versus oral tamoxifen Plaque area (mm²) Curvature (degrees)PLC Tamoxifen PLC Tamoxifen Before After Before After Before AfterBefore After 25.6 ± 19.2 ± 26.8 ± 25.2 ± 25.31 ± 20.06 ± 24.31 ± 23.06 ±4.02 4.26 3.83 3.99 4.01 3.51 4.84 5.40 Signifi- Source of Sum of Meancance variation squares d.o.f. squares F value F crit Analysis ofvariance of plaque area pre- and post-therapy Pre-/post- 320 1 32019.70188 3.02E−05 3.966761 Therapy Patients 259.2 1 259.2 15.958520.000148 3.966761 Interaction 115.2 1 115.2 7.092677 0.009444 3.966761In 1234.4 76 16.24211 Total 1928.8 79 Analysis of variance of penilecurvature pre- and post-therapy Pre-/post- 169 1 169 8.34739 0.005364.00119 therapy Patients 16 1 16 0.79028 0.37756 4.00119 Interaction 641 64 3.16114 0.08047 4.00119 In 1214.75 60 20.2458 Total 1463.75 63

EXAMPLE 2

Oral Tamoxifen Versus Intramuscular Propionyl L-Carnitine

30 subjects (mean age 50, range 42-63) with induratio penis plastica inthe early chronic stage were randomised to two groups of 15 patientseach. The first group was submitted to therapy with intramuscularpropionyl L-carnitine 300×2 mg/day for 3 months, and the second group totherapy with oral tamoxifen 20×2 mg/day. The variables measured wereplaque area (in all subjects) and penile curvature, which was present in12 subjects per group. It was found that intramuscular propionylL-carnitine reduces the plaque area and the curvature of theartificially erect penis to a significantly greater extent thantamoxifen. Intraplaque verapamil was not used in these patients.

The results are presented in Table 2, where the data are expressed asmean±standard deviation (S.D.). TABLE 2 Plaque area (mm²) Curvature(degrees) PLC Tamoxifen PLC Tamoxifen Before After Before After BeforeAfter Before After 11.1 ± 6.47 ± 11.6 ± 9.07 ± 17.75 ± 13.00 ± 18.08 ±16.58 ± 4.16 3.79 3.48 3.71 3.57 4.71 5.63 5.53 Signifi- Source of Sumof Mean cance variation squares d.o.f. squares F value F crit Analysisof variance of plaque area Pre-/Post- 190.8 1 190.82 13.23802 0.000594.012975 Therapy Patients 36.8 1 36.82 2.554179 0.115631 4.012975Interaction 16 1 16.02 1.111166 0.296356 4.012975 In 807.2 56 14.41Total 1050.85 59 Analysis of variance of penile curvature in degreesPre-Post 117.19 1 117.19 4.81855 0.033475 4.061704 Patients 46.02 146.02 1.892298 0.175906 4.067045 Interaction 31.69 1 31.69 1.3029360.259852 4.061704 In 1070.08 44 24.32 Total 1264.98 47

EXAMPLE 3

Intraplaque Triamcinolone Acetonide Versus Intraplaque PropionylL-Carnitine.

In this case 34 the study population consisted of 34 patients (mean age50, range 44-63) with induratio penis plastica in the chronic stage, whopresented an irremediable intolerance to intraplaque verapamil.

17 were submitted to intraplaque infiltrations with propionylL-carnitine 300 mg, 1 infiltration per week for 10 weeks, and 17 tointraplaque infiltrations with triamcinolone acetonide 40 mg (Kenacort®Squibb), 1 infiltration per week for 10 weeks. The variables measuredwere plaque area in mm² by dynamic colour Doppler ultrasonography andthe curvature of the artificially erect penis in degrees.

Intraplaque propionyl L-carnitine proved significantly more active thantriamcinolone acetonide.

The results are presented in Table 3, where the data are expressed asmean±standard deviation (S.D.). TABLE 3 Plaque area (mm²) Curvature(degrees) PLC Triamcinolone PLC Triamcinolone Before After Before AfterBefore After Before After 26.65 ± 15.47 ± 25.23 ± 25.35 ± 20.38 ± 14.77± 22.69 ± 23.15 ± 3.93 4.54 4.18 6.36 3.75 5.21 4.71 3.28 Signifi-Source of Sum of Mean cance variation squares d.o.f. squares F value Fcrit Analysis of variance of plaque area Pre-/post- 519.75 1 519.7622.10209 1.42E−05 3.99092 therapy Patients 304.94 1 304.94 12.967090.000619 3.99092 Interaction 542.12 1 542.12  1.111166 9.86E−06 3.99092In 1505.06 64 23.52 Total 2871.88 67 Analysis of variance of penilecurvature in degrees Pre-/post- 86.33 1 86.33  4.646196 0.0361664.042647 therapy Patients 371.56 1 371.56 19.99758 4.74E−05 4.042647Interaction 120.02 1 120.02  6.459548 0.01432 4.042647 In 891.85 4818.58 Total 1469.76 51

The examples continue with the use of oral propionyl L-carnitinecombined with verapamil. These studies were conducted in most of thepatients tested and therefore the analysis could be carried out on alarge number of variables.

EXAMPLE 4

Advanced La Peyronie's Disease

The study was conducted according to a randomised double-blind protocol.

In all, a total of 60 patients with advanced La Peyronie's disease wereexamined (mean age 59 years, range 42-64 years) and randomised to twogroups of 30. The disease was diagnosed and studied by means of historytaking, physical examination, pharmacologically induced erection,photography of the erect penis, basal and dynamic colour Dopplerultrasonography of the penile cavernous arteries, and administration ofthe “International Index of Erectile Function” (I.I.E.F. 15)Questionnaire (Rosen R. C., et al.: Urology 49: 822-830, 1997). Thepatients were submitted to 10 intraplaque infiltrations (1 infiltrationa week) with 10 mg of verapamil (Levine L. A.: J. Urol. 158: 1395-1399,1997). The first group received propionyl L-carnitine 1×2 g/day for 3months, and the second group tamoxifen 20×2 mg/day for 3 months. Thedata were collected 6 months after the end of therapy when the initialhistory taking and semeiological examination were repeated.

EXAMPLE 5

La Peyronie's Disease Resistant to Other Therapies

The study was conducted with a before-after prospective design. In thislast group of subjects it proved impossible to adopt a case-controldesign owing to the large number of treatments to which they had beensubjected.

In all, a total of 15 patients (mean age 56, range 39-63) were treatedfor La Peyronie's disease which continued to progress despite previoustherapies. Details of the previous therapies are as follows: intraplaqueverapamil (I.V.) administration according to the protocol proposed byLevine (ibid.; tamoxifen (T) 20×2 mg/day for 3 months; vitamin E (E)200-400 mg/day for 3 months; extracorporeal shock wave therapy(E.C.S.W.), delivered using the Minilith SLI device, with 3000-4000shocks per session for 6 sessions; iontophoresis (Itf) administered in12 sessions (3 sessions a week) using verapamil and dexamethasone at thepositive pole for 20 minutes. Five patients had been treated withIV+Itf+ECSW, 5 patients with (IV+T)+Itf+ECSW, 2 with IV+(IV+E)+Itf+ECSW,1 with (IV+T)+(IV+E)+Itf+ECSW and 2 with (IV+E)+Itf+ECSW.

The disease was diagnosed and studied as indicated above. The patientswere submitted to 10 intraplaque infiltrations (1 infiltration per week)with 10 mg of verapamil and to the oral administration of propionylL-carnitine 1×2 g/day for 3 months. The data were collected 6 monthsafter the end of the therapy when the initial history taking andsemeiological examination were repeated.

The following variables were compared between groups and/or before andafter therapy.

-   -   I. Pain on erection, quantified according to the international        pain scale (Beers M. H., Fietcher M. B.: The Merck Manual. 17th        edition. West Point: Merck and Co. 1999) (0=no pain; 1=mild        pain; 2=moderate pain; 3=severe pain) with the results        classified as positive or negative according to whether the        score decreases or increases;    -   II. Penile curvature measured in degrees on a photograph taken        in the outpatients' department during a pharmacologically        induced full erection;    -   III. Plaque area measured in mm² by ultrasonography performed        during a pharmacologically induced full erection;    -   IV. I.I.E.F. 15 score;    -   V. Peak systolic velocity (PSV) (cm/sec), end-diastolic velocity        (EDV) (cm/sec) and the resistivity index (RI) of the right and        left cavernous arteries using dynamic Doppler ultrasonography;    -   VI. Progression of the disease defined as an increase in the        curvature and/or plaques and/or EDV and/or a reduction of the RI        and/or PSV and/or I.I.E.F. 15 score, the results being defined        as absence or presence of disease progression;    -   VII. Need for penis straightening surgery and/or for        straightening and a prosthesis, the results being classified as        presence or absence of any such need;    -   VIII. Side effects classified as presence or absence of side        effects.

Data Analysis

The data relating to pain, disease progression, need for surgery andside effects were compared before and 6 months after therapy using thechi-square test. Differences in plaque area, penile curvature, I.I.E.F.15 score, PSV, EDV and RI were calculated between groups and 6 monthsafter therapy with 2×2 factorial analysis of variance in the case ofadvanced La Peyronie's disease, or with analysis of variance forrandomised blocks (1 patient=1 block) in patients with La Peyronie'sdisease resistant to therapy in order to check for individual variablesthat might have altered the analysis. The RI data were subjected toangular transformation [sin⁻¹ (p/100)], whereas in all other casesnatural data were used (Armitage P.: Statistical Methods in MedicalResearch London: Blackwell Scientific Publications 1971).

Advanced La Peyronie's Disease

29 (96.7%) patients in group 1 presented a reduction of pain and onlyone (3.3%) showed no such reduction; exactly the same results wereobtained in group 2 (chi-square=0, P not significant).

The combination of verapamil plus propionyl L-carnitine was found tosignificantly reduce penile curvature (Table 4) and plaque area (Table5) and to significantly increase the I.I.E.F. 15 score (Table 6). Theeffects of verapamil plus propionyl L-carnitine on the right and leftcavernous arteries are presented in Tables 7 and 8, respectively. Thispharmacological combination proved capable of significantly reducing EDVand increasing the RI. The combination of tamoxifen and verapamil had nosignificant effect on any of these variables. Neither of the twocombinations showed any activity on PSV. One patient out of 30 in group1 required surgery, while in group 2 an operation was recommended in 8out of 30 cases (chi-square=4.615; P<0.05). None of the patients ingroup 1 presented progression of the disease, whereas there were 6 casesof disease progression in group 2 (chi-square=4.615; P<0.05). No sideeffects were observed in group 1 as against 6 cases in group 2(chi-square=4.615; P<0.05), namely, 3 cases of slight epigastric painand 3 of slight loss of libido. None of the patients had to discontinuethe therapy owing to side effects.

La Peyronie's Disease Resistant to Therapies

Nine patients out of 15 were still experiencing pain before beingadministered intraplaque verapamil and oral propionyl L-carnitine; afterthis therapy only 1 out of 15 had pain (chi-square=7.35, P<0.01). Thecombination of verapamil and propionyl L-carnitine was found tosignificantly reduce penile curvature (Table 9) and plaque area (Table10), and to significantly increase the I.I.E.F. 15 score (Table 11). Theeffects of verapamil and propionyl L-carnitine on the right and leftcavernous arteries are presented in Tables 12 and 13, respectively. Thispharmacological combination proved capable of significantly reducing EDVand increasing the RI, whereas it had no effect on PSV. Three patientsrequired surgery and 1 presented progression of the disease. TABLE 4Comparison of penile curvature in degrees before and after therapyPenile curvature in degrees Mean ± S.D. Group 1 Group 2 Before therapy39.4 ± 4.2 38.5 ± 36.6 After therapy 27.6 ± 6.7 36.6 ± 5.6 Analysis ofvariance (d.o.f. = degrees of freedom; n.s. = not significant) Source ofSum of Mean Variation squares d.o.f. Squares F P Treatments 504.3 1504.3 16.7484 <0.01 Pre- post-therapy 1400.83 1 1400.83 46.52332 <0.01Interaction 740.03 1 740.03 24.57738 <0.01 Error 3492.8 116 30.11

TABLE 5 Comparison of plaque areas in mm² before and after therapyPlaque area in mm² Mean ± S.D. Group 1 Group 2 Before therapy 31.8 ± 4.633.2 ± 4.6 After therapy 24.2 ± 5.51 31.9 ± 7.6 Analysis of variance(d.o.f. = degrees of freedom; n.s. = not significant) Sum of Mean Sourceof variation Squares d.o.f. squares F P Treatments 590.07 1 590.0718.02315 <0.01 Pre-/post-therapy 621.07 1 621.07 18.84228 <0.01Interaction 285.21 1 285.20  8.652269 <0.01 Error 3823.57 116 32.96

TABLE 6 Comparison of I.I.E.F. 15 Questionnaire scores before and aftertherapy Mean ± S.D. Group 1 Group 2 Before therapy 19.0 ± 5.7 18.2 ± 5.9After therapy 27.0 ± 3.3 18.6 ± 7.8 Analysis of variance (d.o.f. =degrees of freedom; n.s. = not significant) Sum of Mean Source ofvariation Squares d.o.f. squares F P Treatments 630.21 630.21 18.0372<0.01 Pre-/post-therapy 525.01 1 525.01 15.02627 <0.01 Interaction429.41 1 429.41 12.2901 <0.01 Error 4052.97 116 34.94

TABLE 7 Comparison of peak systolic velocity (PSV) (cm/sec),end-diastolic velocity (EDV) (cm/sec.) and the resistivity index (RI)(%) of the right cavernous artery before and after therapy. PSV cm/sec.EDV cm/sec. RI %. Mean ± S.D. Mean ± S.D. Mean ± S.D. Group Group GroupGroup Group Group 1 2 1 2 1 2 Before therapy 34.7 ± 35.3 ± 15.6 ± 14.5 ±47.5 ± 49.8 ± 4.5 4.6 5.2 4.8 10.6 10.2 After therapy 34.8 ± 35.3 ± 7.3± 12.9 ± 62.7 ± 51.7 ± 5.2 5.0 3.9 6.2 9.6 15.0 Sum of Mean Source ofvariation squares d.o.f. squares F P PSV: Analysis of variance (d.o.f. =degrees of freedom; n.s. = not significant) Treatments 0.13 1 0.13 <1n.s. Pre-/post-therapy 9.63 1 9.63 <1 n.s. Interaction 0 1 0 <1 n.s.Error 2854.2 116 24.61 EDV: Analysis of variance (d.o.f. = degrees offreedom; n.s. = not significant) Treatments 151.87 1 151.87 5.82326<0.05 Pre-/post-therapy 715.41 1 715.41 27.4305 <0.01 Interaction 336.671 336.67 12.9085 <0.01 Error 3025.37 116 26.08 RI: Analysis of variance(d.o.f. = degrees of freedom; n.s. = not significant) Treatments 2211.831 2211.83 16.4886 <0.01 Pre-/post-therapy 566.60 1 566.60 4.22383 <0.05Interaction 1328.52 1 1328.52 12.90895 <0.01 Error 15560.61 116 134.1431

TABLE 8 Comparison of peak systolic velocity (PSV) (cm/sec),end-diastolic velocity (EDV) (cm/sec.) and the resistivity index (RI)(%) of the left cavernous artery before and after therapy PSV cm/sec.EDV. cm/sec. RI % Mean ± S.D. Mean ± S.D. Mean ± S.D. Group Group GroupGroup Group Group 1 2 1 2 1 2 Before therapy 34.7 ± 34.9 ± 15.5 ± 14.1 ±47.6 ± 50.5 ± 4.3 4.3 4.9 5.0 10.1 10.8 After therapy 34.6 ± 34.6 ± 7.5± 13.6 ± 62.6 ± 50.0 ± 4.6 4.7 4.2 6.0 10.0 15.0 Sum of Mean Source ofvariation squares d.o.f. squares F P PSV: Analysis of variance (d.o.f. =degrees of freedom; n.s. = not significant) Treatments 0.21 1 0.21 <1n.s. Pre-/post-therapy 0.675 1 0.67 <1 n.s. Interaction 0.21 1 0.21 <1n.s. Error 2337.7 116 20.15 EDV: Analysis of variance (d.o.f. = degreesof freedom; n.s. = not significant) Treatments 165.75 1 165.67 6.474805<0.05 Pre-/post-therapy 541.87 1 541.875 21.17721 <0.01 Interaction421.87 1 421.875 16.48745 <0.01 Error 2968.16 116 25.58764 RI: Analysisof variance (d.o.f. = degrees of freedom; n.s. = not significant)Treatments 715.66 1 715.66 5.247219 <0.05 Pre-/post-therapy 1563.33 11563.33 11.46229 <0.01 Interaction 1780.02 1 1780.02 13.05102 <0.01Error 158212.17 116 136.39

TABLE 9 Comparison of penile curvature in degrees before and aftertherapy in resistant cases Before therapy After Mean ± S.D. therapyPenile curvature 42.0 ± 5.1 37.5 ± 6.0 in degrees Mean ± S.D. Analysisof variance (d.o.f. = degrees of freedom; n.s. = not significant) Sum ofMean Source of variation squares d.o.f. squares F P Patients 811.66 1457.99 13.1228 <0.01 Treatments 149.63 1 149.63 33.8609 <0.001 Error61.87 14 4.419048

TABLE 10 Comparison of plaque area in mm² before and after therapy inresistant cases Before therapy After Mean ± S.D. therapy Plaque area in38.5 ± 4.9 32.7 ± 6.4 mm². Mean ± S.D. Analysis of variance (d.o.f. =degrees of freedom; n.s. = not significant) Sum of Mean Source ofvariation squares d.o.f. squares F P Patients 813.2 14 58.09 9.981997<0.01 Treatments 246.53 1 246.53 42.36661 0.001 Error 81.46 14 5.82

TABLE 11 Comparison of I.I.E.F. 15 Questionnaire scores for penilecurvature in degrees before and after therapy in resistant cases Beforetherapy After Mean ± S.D. therapy I.I.E.F. 15. score 20.5 ± 3.6 26.5 ±4.0 Mean ± S.D. Analysis of variance (d.o.f. = degrees of freedom; n.s.= not significant) Sum of Mean Source of variation squares d.o.f.squares F P Patients 244.47 14 17.46 1.55711 n.s. Treatments 270.0 1 27024.0764 <0.01 Error 157.0 14 11.21

TABLE 12 Comparison of peak systolic velocity (PSV) (cm/sec),end-diastolic velocity (EDV) (cm/sec.) and the resistivity index (RI)(%) of the right cavernous artery before and after therapy in resistantcases Before therapy After therapy PSV cm/sec. 40.5 ± 6.0 40.5 ± 5.4Mean ± S.D. EDV cm/sec. 14.8 ± 5.9  7.3 ± 5.1 Mean ± S.D. RI % 53.2 ±8.3 65.2 ± 10.1 Mean ± S.D. Sum of Mean Source of variation squaresd.o.f. squares F P PSV: Analysis of variance (d.o.f. = degrees offreedom; n.s. = not significant) Patients 887 14 63.36 36.25341 <0.01Treatments 0.03 1 0.03 <1 n.s. Error 24.47 14 1.75 EDV: Analysis ofvariance (d.o.f. = degrees of freedom; n.s. = not significant) Patients401.87 14 28.70 <1 n.s. Treatments 418.13 1 418.13 13.36906 <0.01 Error437.87 14 31.28 RI: Analysis of variance (d.o.f. = degrees of freedom;n.s. = not significant) Patients 1203.20 14 85.94 1.002293 n.s.Treatments 1073.16 1 107.16 12.51548 <0.01 Error 1200.45 14 85.75

TABLE 13 Comparison of peak systolic velocity (PSV) (cm/sec),end-diastolic velocity (EDV) (cm/sec) and the resistivity index (RI) (%)of the left cavernous artery before and after therapy in resistant casesBefore therapy After therapy PSV cm/sec. 40.1 ± 6.5 40.0 ± 6.6 Mean ±S.D. EDV cm/sec. 14.1 ± 4.5  8.3 ± 4.7 Mean ± S.D. RI % 53.3 ± 8.1 63.0± 9.8 Mean ± S.D. Sum of Mean Source of variation squares d.o.f. squaresF P PSV: Analysis of variance (d.o.f. = degrees of freedom; n.s. = notsignificant) Patients 1190.47 14 85.03 140.61 <0.01 Treatments 0.03 10.03 <1 n.s. Error 8.47 14 0.60 EDV: Analysis of variance (d.o.f. =degrees of freedom; n.s. = not significant) Patients 318.8 14 22.771.55631 n.s. Treatments 258.1333 1 258.13 13.10005 <0.01 Error 275.866714 19.70 RI; Analysis of variance (d.o.f. = degrees of freedom; n.s. =not significant) Patients 1377.89 14 98.42 1.567343 n.s. Treatments703.61 1 703.61 11.20598 <0.01 Error 879.13 14 62.79

Propionyl L-carnitine proved significantly more active than combinedtamoxifen and verapamil in relation to almost all the datacharacterising the disease and presented significantly fewer sideeffects. The apparent lack of activity of tamoxifen plus verapamil isdue to the fact that the analysis of variance considers the entire panelof results embracing patients that improve, patients that remain stableand patients in whom the disease progresses. In actual fact, thecombination of tamoxifen and verapamil arrested the progression ofadvanced La Peyronie's disease in 80% of cases (propionyl L-carnitineplus verapamil achieved significantly better results); advanced LaPeyronie's disease, if left untreated, will progress in 90% of cases.

Advanced La Peyronie's disease is often associated with an erectiledeficit (low I.I.E.F. 15 score). It is of no importance that neither ofthe pharmacological combinations proved effective on PSV, which is anindicator of patency of the arteries, since these are generallyunimpaired in La Peyronie's disease. What is important, on the otherhand, is the major activity on EDV, which measures venous resistance:the lower the EDV, the higher the resistance of the veins to blood flowor, in other words, the higher the resistivity index which is calculatedas follows: R.I.=PSV-EDV/PSV×100. The fact that the erectile activity ofpropionyl L-carnitine and verapamil manifested itself in the form of anaction on EDV confirms the assumption that the erectile deficit ofPetronie's disease is secondary to a venous deficiency.

In parallel tests the combination of propionyl L-carnitine plusverapamil proved significantly more active than the combination ofacetyl L-carnitine plus verapamil, as demonstrated by the next example.

EXAMPLE 6

20 subjects (mean age 48, range 40-61) with induratio penis plastica atan advanced chronic stage were randomised to two groups of 10 patientseach. The first group was submitted to therapy with oral propionylL-carnitine (PLC) 1×2 g/day 3 months and intraplaque verapamil 10 mg (10infiltrations, 1 a week), while the second group was submitted totherapy with oral acetyl L-carnitine (ALC) 1×2 g/day for 3months+intraplaque verapamil 10 mg (10 infiltrations, 1 a week). Thevariables measured were plaque area by dynamic colour Doppler penileultrasonography. In view of the limited number of subjects in the sampleit was not possible to carry out any analysis of other data; in anyevent, the size of the plaque is the most important variable whenmonitoring La Peyronie's disease, since all the other symptoms depend onthe extent of the plaque (Belgrano, ibid.). It was found that propionylL-carnitine plus intraplaque verapamil reduce the plaque area to asignificantly greater extent than acetyl L-carnitine plus intraplaqueverapamil.

The results are presented in Table 14, where the data are expressed asmean±standard deviation (S.D.). TABLE 14 Plaque area (mm²) PLC ALCBefore After Before After 16.4 + 7.9 ± 16.3 ± 11.8 ±  3.13 1.79  2.75 1.81 Analysis of variance of plaque area Signifi- Source of Sum of Meancance variation squares d.o.f. squares F value F crit Treatment 422.5 1422.5 70.74419 5.12E−10 4.113161 Pre-/post 36.1 1 36.1  6.0446510.018891 4.113161 Interaction 40 1 40  6.697674 0.013835 4.113161 Error215 36 5.972222 Total 713.6 39

Propionyl L-carnitine, particularly in combination with verapamil, isthe only drug to have proved efficacious in the therapy of resistant LaPeyronie's disease which progresses despite previous therapies.

Propionyl L-carnitine is the only orally administered drug to haveproved capable of boosting the action of intraplaque verapamil in thetherapy of advanced La Peyronie's disease.

1. Use of propionyl L-carnitine or one of its pharmaceuticallyacceptable salts for the preparation of a medicine useful for thetreatment of La Peyronie's disease.
 2. Use according to claim 1, inwhich said medicine is suitable for oral administration.
 3. Useaccording to claim 1, in which said medicine is suitable forintramuscular, intravenous and intraplaque administration.
 4. Useaccording to claim 1, in which said La Peyronie's disease is at anadvanced stage.
 5. Use according to claim 1, in which said La Peyronie'sdisease is resistant to conventional therapies.
 6. Combination ofpropionyl L-carnitine, or one of its pharmaceutically acceptable salts,and an active ingredient useful for the treatment of La Peyronie'sdisease selected from the group consisting of tamoxifen, triamcinoloneand verapamil.
 7. Pharmaceutical composition containing the combinationof claim 6 and vehicles and or excipients, if any.
 8. Pharmaceuticalcomposition of claim 7, in which said combination is suitable for thecoordinated use.
 9. Use of an active ingredient useful for the treatmentof La Peyronie's disease, in combination with propionyl L-carnitine orone of its pharmaceutically acceptable salts, for the preparation of amedicine useful for the treatment of La Peyronie's disease.
 10. Useaccording to claim 9, where said active ingredient is selected from thegroup consisting of tocopherols, vitamin E, allopurinol, potassiumamino-benzoate, tamoxifen, immunomodulators, triamcinolone, andverapamil.
 11. Use according to claim 3 in which said medicine issuitable for oral, intramuscular, intravenous and intraplaqueadministration.
 12. Use according to claim 3, in which said medicine issuitable for the co-ordinated use of said combination.
 13. Use accordingto claim 3, in which said medicine is suitable for the oraladministration of propionyl L-carnitine and for the intraplaqueadministration of verapamil.
 14. Use according to claim 3, in which saidmedicine is suitable for the oral administration of 1 g of propionylL-carnitine, or an equivalent amount of one of its pharmaceuticallyacceptable salts, per dosage unit, and for the intraplaqueadministration of 10 mg of verapamil.
 15. Use according to claim 3, inwhich said La Peyronie's disease is at an advanced stage.
 16. Useaccording to claim 3, in which said La Peyronie's disease is resistantto conventional therapies.